A sodium hyaluronate solution is used as a therapeutic agent for arthritis such as osteoarthritis of knee (OA) or rheumatoid arthritis of knee (RA). The sodium hyaluronate solution is generally used as injections by the direct administration to the affected knee joints, and shoulder joints, and frequently used for the purpose of improving functional disorders and suppressing pain caused by the arthritis.
Non-steroidal anti-inflammatory drugs (hereinafter also referred to as “NSAIDs” or “NSAID”) and disease-modifying anti-rheumatic drugs (hereinafter also referred to as “DMARD”), which improve morbid states such as articular rheumatism, are also used as agents for suppressing or alleviating pains caused by such arthritis. In general, these NSAIDs are orally administered in many cases, and there are also frequent cases in which concomitant use of the injection of the above-described sodium hyaluronate solution and oral administration of NSAIDs. In the case of the oral administration of these NSAIDs, there is a problem in that the greater part of the NSAIDs are metabolized while circulating in the blood stream before they reach the affected site. To circumvent this problem, high dosage of NSAIDs are necessary to maintain effective concentration in the blood in order to deriver NSAIDs to the affected part. However, such high dosage of NSAIDs by the oral administration causes serious gastrointestinal adverse effects.
In addition, immunotherapy agents (immunomodulators and immunosuppressants) are used as DMARD for controlling immune abnormality or the like which is considered to be a cause of inflammation.
On the other hand, Hyaluronic acid is a polysaccharide constituted by a repeating structure with a disaccharide unit of N-acetyl-D-glucosamine and D-glucuronic acid as the basic core structure, and it is known to be highly hydrophilic due to the carboxyl group and a number of hydroxyl group in the disaccharide unit. As an example that hyaluronic acid has hydrophilic property, namely high hydration with water molecule, hyaluronic acid can hold water about 1,000-fold larger than its own weight. However, when highly hydrophobic agents such as NSAIDs are introduced into hyaluronic acid having such a high hydrophilic property, it is conventionally known that hydrophobic property of hyaluronic acid molecule itself increases so that water-semi-insoluble gel or insoluble matter are formed. Consequently, those water-semi-insoluble gel or insoluble matter are not suitable for the injectable use. Furthermore, with the increase of the degree of substitution of medicament for the purpose of longer sustained release, the insolubility is also increased so that it takes a form inappropriate as injections.
As an example in which not only NSAIDs but also other medicaments were introduced into hyaluronic acid, there is a report on a conjugate in which a matrix metalloproteinase inhibitor (MMP inhibitor) as an arthritis treating agent and hyaluronic acid were bound to each other via a spacer or not via the spacer (Patent Reference 1). However, as a suitable binding mode of the MMP inhibitor with hyaluronic acid, stronger covalent bond is exemplified in the report, and it suggests that a synergistic medicament effect of the action of the MMP inhibitor and the effect of hyaluronic acid can be expected on the assumption that the conjugate are not dissociated and degraded into the MMP inhibitor and hyaluronic acid in the administered region. In addition, it exemplifies carboxyl group as the binding region with hyaluronic acid, however, the degree of substitution of the medicament to the carboxyl group is considerably low, or a treatment for keeping suitable embodiment (solution) as injections is not carried out.
As other examples, there is a case in which hyaluronic acid is activated with water-soluble carbodiimide, and nucleophilic reagents were allowed to react therewith (Patent Reference 2), but these medicaments were not NSAIDs, and the final dosage form was an insoluble film. In addition, there is a case in which various medicaments were introduced into hyaluronic acid using a halogenated di-lower alkylphosphinothioyl (Rpt-X) as the condensing agent (Patent Reference 3), but dosage forms of the prepared derivatives are not described, and a treatment for enabling them as solution in the preparation is not included in the process.
Patent Reference 1: WO 99/59603
Patent Reference 2: JP-T-3-502704
Patent Reference 3: JP-A-9-188705